Role of Non-conventional T Lymphocytes in Respiratory Infections: The Case of the Pneumococcus

Non-conventional T lymphocytes constitute a special arm of the immune system and act as sentinels against pathogens at mucosal surfaces. These non-conventional T cells (including mucosal-associated invariant T [MAIT] cells, gamma delta [γδ] T cells, and natural killer T [NKT] cells) display several innate cell-like features and are rapidly activated by the recognition of conserved, stress-induced, self, and microbial ligands. Here, we review the role of non-conventional T cells during respiratory infections, with a particular focus on the encapsulated extracellular pathogen Streptococcus pneumoniae, the leading cause of bacterial pneumonia worldwide. We consider whether MAIT cells, γδ T cells, and NKT cells might offer opportunities for preventing and/or treating human pneumococcus infections.

Vyšlo v časopise: Role of Non-conventional T Lymphocytes in Respiratory Infections: The Case of the Pneumococcus. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004300
Kategorie: Review


Non-conventional T lymphocytes constitute a special arm of the immune system and act as sentinels against pathogens at mucosal surfaces. These non-conventional T cells (including mucosal-associated invariant T [MAIT] cells, gamma delta [γδ] T cells, and natural killer T [NKT] cells) display several innate cell-like features and are rapidly activated by the recognition of conserved, stress-induced, self, and microbial ligands. Here, we review the role of non-conventional T cells during respiratory infections, with a particular focus on the encapsulated extracellular pathogen Streptococcus pneumoniae, the leading cause of bacterial pneumonia worldwide. We consider whether MAIT cells, γδ T cells, and NKT cells might offer opportunities for preventing and/or treating human pneumococcus infections.


1. BartlettJG, BreimanRF, MandellLA, FileTMJr (1998) Community-acquired pneumonia in adults: guidelines for management. The Infectious Diseases Society of America. Clin Infect Dis 26: 811–838.

2. FileTM (2003) Community-acquired pneumonia. Lancet 362: 1991–2001.

3. WroePC, FinkelsteinJA, RayGT, LinderJA, JohnsonKM, et al. (2012) Aging population and future burden of pneumococcal pneumonia in the United States. J Infect Dis 205: 1589–1592.

4. WelteT, TorresA, NathwaniD (2012) Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax 67: 71–79.

5. ObaroS, AdegbolaR (2002) The pneumococcus: carriage, disease and conjugate vaccines. J Med Microbiol 51: 98–104.

6. KadiogluA, WeiserJN, PatonJC, AndrewPW (2008) The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease. Nat Rev Microbiol 6: 288–301.

7. van der PollT, OpalSM (2009) Pathogenesis, treatment, and prevention of pneumococcal pneumonia. Lancet 374: 1543–1556.

8. VernatterJ, PirofskiLA (2013) Current concepts in host-microbe interaction leading to pneumococcal pneumonia. Curr Opin Infect Dis 26: 277–283.

9. MitchellAM, MitchellTJ (2010) Streptococcus pneumoniae: virulence factors and variation. Clin Microbiol Infect 16: 411–418.

10. McCullersJA (2006) Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev 19: 571–582.

11. van der SluijsKF, van der PollT, LutterR, JuffermansNP, SchultzMJ (2010) Bench-to-bedside review: bacterial pneumonia with influenza - pathogenesis and clinical implications. Crit Care 14: 219.

12. ViasusD, Garcia-VidalC, CarratalaJ (2013) Advances in antibiotic therapy for community-acquired pneumonia. Curr Opin Pulm Med 19: 209–215.

13. HackelM, LascolsC, BouchillonS, HiltonB, MorgensternD, et al. (2013) Serotype prevalence and antibiotic resistance in Streptococcus pneumoniae clinical isolates among global populations. Vaccine 31: 4881–4887.

14. KydJM, McGrathJ, KrishnamurthyA (2011) Mechanisms of bacterial resistance to antibiotics in infections of COPD patients. Curr Drug Targets 12: 521–530.

15. LopezAD, ShibuyaK, RaoC, MathersCD, HansellAL, et al. (2006) Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J 27: 397–412.

16. LevineOS, O'BrienKL, KnollM, AdegbolaRA, BlackS, et al. (2006) Pneumococcal vaccination in developing countries. Lancet 367: 1880–1882.

17. RodgersGL, KlugmanKP (2011) The future of pneumococcal disease prevention. Vaccine 29 Suppl 3: C43–48.

18. DavisSM, Deloria-KnollM, KassaHT, O'BrienKL (2013) Impact of pneumococcal conjugate vaccines on nasopharyngeal carriage and invasive disease among unvaccinated people: Review of evidence on indirect effects. Vaccine 32: 133–145.

19. BogaertD, HermansPW, AdrianPV, RumkeHC, de GrootR (2004) Pneumococcal vaccines: an update on current strategies. Vaccine 22: 2209–2220.

20. HausdorffWP, BryantJ, ParadisoPR, SiberGR (2000) Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin Infect Dis 30: 100–121.

21. TreinerE, DubanL, BahramS, RadosavljevicM, WannerV, et al. (2003) Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422: 164–169.

22. MartinE, TreinerE, DubanL, GuerriL, LaudeH, et al. (2009) Stepwise development of MAIT cells in mouse and human. PLoS Biol 7: e54.

23. GoldMC, CerriS, Smyk-PearsonS, CanslerME, VogtTM, et al. (2010) Human mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol 8: e1000407.

24. DusseauxM, MartinE, SerriariN, PeguilletI, PremelV, et al. (2011) Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117: 1250–1259.

25. TilloyF, TreinerE, ParkSH, GarciaC, LemonnierF, et al. (1999) An invariant T cell receptor alpha chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted alpha/beta T cell subpopulation in mammals. J Exp Med 189: 1907–1921.

26. PorcelliS, YockeyCE, BrennerMB, BalkSP (1993) Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain. J Exp Med 178: 1–16.

27. Kjer-NielsenL, PatelO, CorbettAJ, Le NoursJ, MeehanB, et al. (2012) MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491: 717–723.

28. Le BourhisL, MartinE, PeguilletI, GuihotA, FrouxN, et al. (2010) Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol 11: 701–708.

29. ChuaWJ, TruscottSM, EickhoffCS, BlazevicA, HoftDF, et al. (2012) Polyclonal mucosa-associated invariant T cells have unique innate functions in bacterial infection. Infect Immun 80: 3256–3267.

30. ChibaA, TajimaR, TomiC, MiyazakiY, YamamuraT, et al. (2012) Mucosal-associated invariant T cells promote inflammation and exacerbate disease in murine models of arthritis. Arthritis Rheum 64: 153–161.

31. GoldMC, LewinsohnDM (2013) Co-dependents: MR1-restricted MAIT cells and their antimicrobial function. Nat Rev Microbiol 11: 14–19.

32. Le BourhisL, MburuYK, LantzO (2013) MAIT cells, surveyors of a new class of antigen: development and functions. Curr Opin Immunol 25: 174–180.

33. BirkinshawRW, Kjer-NielsenL, EckleSB, McCluskeyJ, RossjohnJ (2014) MAITs, MR1 and vitamin B metabolites. Curr Opin Immunol 26: 7–13.

34. GapinL (2014) Check MAIT. J Immunol 192: 4475–4480.

35. Le BourhisL, DusseauxM, BohineustA, BessolesS, MartinE, et al. (2013) MAIT cells detect and efficiently lyse bacterially-infected epithelial cells. PLoS Pathog 9: e1003681.

36. GoldMC, EidT, Smyk-PearsonS, EberlingY, SwarbrickGM, et al. (2013) Human thymic MR1-restricted MAIT cells are innate pathogen-reactive effectors that adapt following thymic egress. Mucosal Immunol 6: 35–44.

37. MeierovicsA, YankelevichWJ, CowleySC (2013) MAIT cells are critical for optimal mucosal immune responses during in vivo pulmonary bacterial infection. Proc Natl Acad Sci U S A 110: E3119–3128.

38. BonnevilleM, O'BrienRL, BornWK (2010) Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol 10: 467–478.

39. KalyanS, KabelitzD (2013) Defining the nature of human gammadelta T cells: a biographical sketch of the highly empathetic. Cell Mol Immunol 10: 21–29.

40. VantouroutP, HaydayA (2013) Six-of-the-best: unique contributions of gammadelta T cells to immunology. Nat Rev Immunol 13: 88–100.

41. WandsJM, RoarkCL, AydintugMK, JinN, HahnYS, et al. (2005) Distribution and leukocyte contacts of gammadelta T cells in the lung. J Leukoc Biol 78: 1086–1096.

42. FerreiraLM (2013) Gammadelta T cells: innately adaptive immune cells? Int Rev Immunol 32: 223–248.

43. TanakaY, SanoS, NievesE, De LiberoG, RosaD, et al. (1994) Nonpeptide ligands for human gamma delta T cells. Proc Natl Acad Sci U S A 91: 8175–8179.

44. TanakaY, MoritaCT, TanakaY, NievesE, BrennerMB, et al. (1995) Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375: 155–158.

45. HintzM, ReichenbergA, AltincicekB, BahrU, GschwindRM, et al. (2001) Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human gammadelta T cells in Escherichia coli. FEBS Lett 509: 317–322.

46. GoberHJ, KistowskaM, AngmanL, JenoP, MoriL, et al. (2003) Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197: 163–168.

47. SpadaFM, GrantEP, PetersPJ, SugitaM, MelianA, et al. (2000) Self-recognition of CD1 by gamma/delta T cells: implications for innate immunity. J Exp Med 191: 937–948.

48. RussanoAM, BassottiG, AgeaE, BistoniO, MazzocchiA, et al. (2007) CD1-restricted recognition of exogenous and self-lipid antigens by duodenal gammadelta+ T lymphocytes. J Immunol 178: 3620–3626.

49. UldrichAP, Le NoursJ, PellicciDG, GherardinNA, McPhersonKG, et al. (2013) CD1d-lipid antigen recognition by the gammadelta TCR. Nat Immunol 14: 1137–1145.

50. BukowskiJF, MoritaCT, BrennerMB (1994) Recognition and destruction of virus-infected cells by human gamma delta CTL. J Immunol 153: 5133–5140.

51. ZengX, WeiYL, HuangJ, NewellEW, YuH, et al. (2012) gammadelta T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen-specific interleukin-17 response. Immunity 37: 524–534.

52. ZhangL, JinN, NakayamaM, O'BrienRL, EisenbarthGS, et al. (2010) Gamma delta T cell receptors confer autonomous responsiveness to the insulin-peptide B:9–23. J Autoimmun 34: 478–484.

53. WillcoxCR, PitardV, NetzerS, CouziL, SalimM, et al. (2012) Cytomegalovirus and tumor stress surveillance by binding of a human gammadelta T cell antigen receptor to endothelial protein C receptor. Nat Immunol 13: 872–879.

54. MartinB, HirotaK, CuaDJ, StockingerB, VeldhoenM (2009) Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31: 321–330.

55. ContiL, CasettiR, CardoneM, VaranoB, MartinoA, et al. (2005) Reciprocal activating interaction between dendritic cells and pamidronate-stimulated gammadelta T cells: role of CD86 and inflammatory cytokines. J Immunol 174: 252–260.

56. DevilderMC, MailletS, Bouyge-MoreauI, DonnadieuE, BonnevilleM, et al. (2006) Potentiation of antigen-stimulated V gamma 9V delta 2 T cell cytokine production by immature dendritic cells (DC) and reciprocal effect on DC maturation. J Immunol 176: 1386–1393.

57. DevilderMC, AllainS, DoussetC, BonnevilleM, ScotetE (2009) Early triggering of exclusive IFN-gamma responses of human Vgamma9Vdelta2 T cells by TLR-activated myeloid and plasmacytoid dendritic cells. J Immunol 183: 3625–3633.

58. PagetC, ChowMT, DuretH, MattarolloSR, SmythMJ (2012) Role of gammadelta T cells in alpha-galactosylceramide-mediated immunity. J Immunol 188: 3928–3939.

59. HaydayAC (2009) Gammadelta T cells and the lymphoid stress-surveillance response. Immunity 31: 184–196.

60. ZhengJ, LiuY, LauYL, TuW (2013) gammadelta-T cells: an unpolished sword in human anti-infection immunity. Cell Mol Immunol 10: 50–57.

61. DieliF, Troye-BlombergM, IvanyiJ, FournieJJ, KrenskyAM, et al. (2001) Granulysin-dependent killing of intracellular and extracellular Mycobacterium tuberculosis by Vgamma9/Vdelta2 T lymphocytes. J Infect Dis 184: 1082–1085.

62. QinG, MaoH, ZhengJ, SiaSF, LiuY, et al. (2009) Phosphoantigen-expanded human gammadelta T cells display potent cytotoxicity against monocyte-derived macrophages infected with human and avian influenza viruses. J Infect Dis 200: 858–865.

63. SuD, ShenM, LiX, SunL (2013) Roles of gammadelta T cells in the pathogenesis of autoimmune diseases. Clin Dev Immunol 2013: 985753.

64. DudalS, TurriereC, BessolesS, FontesP, SanchezF, et al. (2006) Release of LL-37 by activated human Vgamma9Vdelta2 T cells: a microbicidal weapon against Brucella suis. J Immunol 177: 5533–5539.

65. HamadaS, UmemuraM, ShionoT, HaraH, KishiharaK, et al. (2008) Importance of murine Vdelta1gammadelta T cells expressing interferon-gamma and interleukin-17A in innate protection against Listeria monocytogenes infection. Immunology 125: 170–177.

66. TuW, ZhengJ, LiuY, SiaSF, LiuM, et al. (2011) The aminobisphosphonate pamidronate controls influenza pathogenesis by expanding a gammadelta T cell population in humanized mice. J Exp Med 208: 1511–1522.

67. LiH, XiangZ, FengT, LiJ, LiuY, et al. (2013) Human Vgamma9Vdelta2-T cells efficiently kill influenza virus-infected lung alveolar epithelial cells. Cell Mol Immunol 10: 159–164.

68. JamesonJM, CruzJ, CostanzoA, TerajimaM, EnnisFA (2010) A role for the mevalonate pathway in the induction of subtype cross-reactive immunity to influenza A virus by human gammadelta T lymphocytes. Cell Immunol 264: 71–77.

69. KistowskaM, RossyE, SansanoS, GoberHJ, LandmannR, et al. (2008) Dysregulation of the host mevalonate pathway during early bacterial infection activates human TCR gamma delta cells. Eur J Immunol 38: 2200–2209.

70. ChengP, LiuT, ZhouWY, ZhuangY, PengLS, et al. (2012) Role of gamma-delta T cells in host response against Staphylococcus aureus-induced pneumonia. BMC Immunol 13: 38.

71. JanisEM, KaufmannSH, SchwartzRH, PardollDM (1989) Activation of gamma delta T cells in the primary immune response to Mycobacterium tuberculosis. Science 244: 713–716.

72. PengMY, WangZH, YaoCY, JiangLN, JinQL, et al. (2008) Interleukin 17-producing gamma delta T cells increased in patients with active pulmonary tuberculosis. Cell Mol Immunol 5: 203–208.

73. LockhartE, GreenAM, FlynnJL (2006) IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol 177: 4662–4669.

74. UmemuraM, YahagiA, HamadaS, BegumMD, WatanabeH, et al. (2007) IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection. J Immunol 178: 3786–3796.

75. Okamoto YoshidaY, UmemuraM, YahagiA, O'BrienRL, IkutaK, et al. (2010) Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung. J Immunol 184: 4414–4422.

76. SaitohT, YanoI, KumazawaY, TakimotoH (2012) Pulmonary TCR gammadelta T cells induce the early inflammation of granuloma formation by a glycolipid trehalose 6,6′-dimycolate (TDM) isolated from Mycobacterium tuberculosis. Immunopharmacol Immunotoxicol 34: 815–823.

77. Scott-BrowneJP, MatsudaJL, MallevaeyT, WhiteJ, BorgNA, et al. (2007) Germline-encoded recognition of diverse glycolipids by natural killer T cells. Nat Immunol 8: 1105–1113.

78. BendelacA, SavagePB, TeytonL (2007) The biology of NKT cells. Annu Rev Immunol 25: 297–336.

79. BerzinsSP, SmythMJ, BaxterAG (2011) Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol 11: 131–142.

80. RossjohnJ, PellicciDG, PatelO, GapinL, GodfreyDI (2012) Recognition of CD1d-restricted antigens by natural killer T cells. Nat Rev Immunol 12: 845–857.

81. BrennanPJ, BriglM, BrennerMB (2013) Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol 13: 101–117.

82. RhostS, LofbomL, RynmarkBM, PeiB, ManssonJE, et al. (2012) Identification of novel glycolipid ligands activating a sulfatide-reactive, CD1d-restricted, type II natural killer T lymphocyte. Eur J Immunol 42: 2851–2860.

83. BerzofskyJA, TerabeM (2009) The contrasting roles of NKT cells in tumor immunity. Curr Mol Med 9: 667–672.

84. ScanlonST, ThomasSY, FerreiraCM, BaiL, KrauszT, et al. (2011) Airborne lipid antigens mobilize resident intravascular NKT cells to induce allergic airway inflammation. J Exp Med 208: 2113–2124.

85. CohenNR, GargS, BrennerMB (2009) Antigen Presentation by CD1 Lipids, T Cells, and NKT Cells in Microbial Immunity. Adv Immunol 102: 1–94.

86. TupinE, KinjoY, KronenbergM (2007) The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol 5: 405–417.

87. FaveeuwC, MallevaeyT, TrotteinF (2008) Role of natural killer T lymphocytes during helminthic infection. Parasite 15: 384–388.

88. TessmerMS, FatimaA, PagetC, TrotteinF, BrossayL (2009) NKT cell immune responses to viral infection. Expert Opin Ther Targets 13: 153–162.

89. BriglM, BrennerMB (2010) How invariant natural killer T cells respond to infection by recognizing microbial or endogenous lipid antigens. Semin Immunol 22: 79–86.

90. PagetC, TrotteinF (2013) Role of type 1 natural killer T cells in pulmonary immunity. Mucosal Immunol 6: 1054–1067.

91. MattnerJ, DebordKL, IsmailN, GoffRD, CantuC3rd, et al. (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434: 525–529.

92. KinjoY, WuD, KimG, XingGW, PolesMA, et al. (2005) Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434: 520–525.

93. KinjoY, TupinE, WuD, FujioM, Garcia-NavarroR, et al. (2006) Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol 7: 978–986.

94. KinjoY, IllarionovP, VelaJL, PeiB, GirardiE, et al. (2011) Invariant natural killer T cells recognize glycolipids from pathogenic Gram-positive bacteria. Nat Immunol 12: 966–974.

95. BriglM, TatituriRV, WattsGF, BhowruthV, LeadbetterEA, et al. (2011) Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J Exp Med 208: 1163–1177.

96. BriglM, BryL, KentSC, GumperzJE, BrennerMB (2003) Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat Immunol 4: 1230–1237.

97. PagetC, MallevaeyT, SpeakAO, TorresD, FontaineJ, et al. (2007) Activation of invariant NKT cells by toll-like receptor 9-stimulated dendritic cells requires type I interferon and charged glycosphingolipids. Immunity 27: 597–609.

98. SalioM, SpeakAO, ShepherdD, PolzellaP, IllarionovPA, et al. (2007) Modulation of human natural killer T cell ligands on TLR-mediated antigen-presenting cell activation. Proc Natl Acad Sci U S A 104: 20490–20495.

99. JohnsonTR, HongS, Van KaerL, KoezukaY, GrahamBS (2002) NK T cells contribute to expansion of CD8(+) T cells and amplification of antiviral immune responses to respiratory syncytial virus. J Virol 76: 4294–4303.

100. De SantoC, SalioM, MasriSH, LeeLY, DongT, et al. (2008) Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J Clin Invest 118: 4036–4048.

101. PagetC, IvanovS, FontaineJ, BlancF, PichavantM, et al. (2011) Potential role of invariant NKT cells in the control of pulmonary inflammation and CD8+ T cell response during acute influenza A virus H3N2 pneumonia. J Immunol 186: 5590–5602.

102. PagetC, IvanovS, FontaineJ, RennesonJ, BlancF, et al. (2012) Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages. J Biol Chem 287: 8816–8829.

103. KokWL, DenneyL, BenamK, ColeS, ClellandC, et al. (2012) Pivotal Advance: Invariant NKT cells reduce accumulation of inflammatory monocytes in the lungs and decrease immune-pathology during severe influenza A virus infection. J Leukoc Biol 91: 357–368.

104. BilenkiL, WangS, YangJ, FanY, JoyeeAG, et al. (2005) NK T cell activation promotes Chlamydia trachomatis infection in vivo. J Immunol 175: 3197–3206.

105. JoyeeAG, QiuH, WangS, FanY, BilenkiL, et al. (2007) Distinct NKT cell subsets are induced by different Chlamydia species leading to differential adaptive immunity and host resistance to the infections. J Immunol 178: 1048–1058.

106. BeharSM, DascherCC, GrusbyMJ, WangCR, BrennerMB (1999) Susceptibility of mice deficient in CD1D or TAP1 to infection with Mycobacterium tuberculosis. J Exp Med 189: 1973–1980.

107. Sada-OvalleI, ChibaA, GonzalesA, BrennerMB, BeharSM (2008) Innate invariant NKT cells recognize Mycobacterium tuberculosis-infected macrophages, produce interferon-gamma, and kill intracellular bacteria. PLoS Pathog 4: e1000239.

108. SkoldM, BeharSM (2003) Role of CD1d-restricted NKT cells in microbial immunity. Infect Immun 71: 5447–5455.

109. SousaAO, MazzaccaroRJ, RussellRG, LeeFK, TurnerOC, et al. (2000) Relative contributions of distinct MHC class I-dependent cell populations in protection to tuberculosis infection in mice. Proc Natl Acad Sci U S A 97: 4204–4208.

110. SzalayG, ZugelU, LadelCH, KaufmannSH (1999) Participation of group 2 CD1 molecules in the control of murine tuberculosis. Microbes Infect 1: 1153–1157.

111. ChackerianA, AltJ, PereraV, BeharSM (2002) Activation of NKT cells protects mice from tuberculosis. Infect Immun 70: 6302–6309.

112. Sada-OvalleI, SkoldM, TianT, BesraGS, BeharSM (2010) Alpha-galactosylceramide as a therapeutic agent for pulmonary Mycobacterium tuberculosis infection. Am J Respir Crit Care Med 182: 841–847.

113. ChibaA, DascherCC, BesraGS, BrennerMB (2008) Rapid NKT cell responses are self-terminating during the course of microbial infection. J Immunol 181: 2292–2302.

114. DieliF, TaniguchiM, KronenbergM, SidobreS, IvanyiJ, et al. (2003) An anti-inflammatory role for V alpha 14 NK T cells in Mycobacterium bovis bacillus Calmette-Guerin-infected mice. J Immunol 171: 1961–1968.

115. ImJS, KangTJ, LeeSB, KimCH, LeeSH, et al. (2008) Alteration of the relative levels of iNKT cell subsets is associated with chronic mycobacterial infections. Clin Immunol 127: 214–224.

116. VeenstraH, BaumannR, CarrollNM, LukeyPT, KiddM, et al. (2006) Changes in leucocyte and lymphocyte subsets during tuberculosis treatment; prominence of CD3dimCD56+ natural killer T cells in fast treatment responders. Clin Exp Immunol 145: 252–260.

117. PatersonGK, MitchellTJ (2006) Innate immunity and the pneumococcus. Microbiology 152: 285–293.

118. KoppeU, SuttorpN, OpitzB (2012) Recognition of Streptococcus pneumoniae by the innate immune system. Cell Microbiol 14: 460–466.

119. HippenstielS, OpitzB, SchmeckB, SuttorpN (2006) Lung epithelium as a sentinel and effector system in pneumonia–molecular mechanisms of pathogen recognition and signal transduction. Respir Res 7: 97.

120. ZhangZ, ClarkeTB, WeiserJN (2009) Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice. J Clin Invest 119: 1899–1909.

121. Elhaik-GoldmanS, KafkaD, YossefR, HadadU, ElkabetsM, et al. (2011) The natural cytotoxicity receptor 1 contribution to early clearance of Streptococcus pneumoniae and to natural killer-macrophage cross talk. PLoS ONE 6: e23472.

122. MitchellAJ, YauB, McQuillanJA, BallHJ, TooLK, et al. (2012) Inflammasome-dependent IFN-gamma drives pathogenesis in Streptococcus pneumoniae meningitis. J Immunol 189: 4970–4980.

123. YamamotoN, KawakamiK, KinjoY, MiyagiK, KinjoT, et al. (2004) Essential role for the p40 subunit of interleukin-12 in neutrophil-mediated early host defense against pulmonary infection with Streptococcus pneumoniae: involvement of interferon-gamma. Microbes Infect 6: 1241–1249.

124. SunK, SalmonSL, LotzSA, MetzgerDW (2007) Interleukin-12 promotes gamma interferon-dependent neutrophil recruitment in the lung and improves protection against respiratory Streptococcus pneumoniae infection. Infect Immun 75: 1196–1202.

125. NakamatsuM, YamamotoN, HattaM, NakasoneC, KinjoT, et al. (2007) Role of interferon-gamma in Valpha14+ natural killer T cell-mediated host defense against Streptococcus pneumoniae infection in murine lungs. Microbes Infect 9: 364–374.

126. McNeelaEA, BurkeA, NeillDR, BaxterC, FernandesVE, et al. (2010) Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog 6: e1001191.

127. YamadaM, GomezJC, ChughPE, LowellCA, DinauerMC, et al. (2011) Interferon-gamma production by neutrophils during bacterial pneumonia in mice. Am J Respir Crit Care Med 183: 1391–1401.

128. WeberSE, TianH, PirofskiLA (2011) CD8+ cells enhance resistance to pulmonary serotype 3 Streptococcus pneumoniae infection in mice. J Immunol 186: 432–442.

129. LuYJ, GrossJ, BogaertD, FinnA, BagradeL, et al. (2008) Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog 4: e1000159.

130. MaJ, WangJ, WanJ, CharboneauR, ChangY, et al. (2010) Morphine disrupts interleukin-23 (IL-23)/IL-17-mediated pulmonary mucosal host defense against Streptococcus pneumoniae infection. Infect Immun 78: 830–837.

131. LiW, MoltedoB, MoranTM (2012) Type I interferon induction during influenza virus infection increases susceptibility to secondary Streptococcus pneumoniae infection by negative regulation of gammadelta T cells. J Virol 86: 12304–12312.

132. CaoJ, WangD, XuF, GongY, WangH, et al. (2014) Activation of IL-27 signalling promotes development of postinfluenza pneumococcal pneumonia. EMBO Mol Med 6: 120–140.

133. KadiogluA, CowardW, ColstonMJ, HewittCR, AndrewPW (2004) CD4-T-lymphocyte interactions with pneumolysin and pneumococci suggest a crucial protective role in the host response to pneumococcal infection. Infect Immun 72: 2689–2697.

134. MalleyR, TrzcinskiK, SrivastavaA, ThompsonCM, AndersonPW, et al. (2005) CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proc Natl Acad Sci U S A 102: 4848–4853.

135. TrzcinskiK, ThompsonCM, SrivastavaA, BassetA, MalleyR, et al. (2008) Protection against nasopharyngeal colonization by Streptococcus pneumoniae is mediated by antigen-specific CD4+ T cells. Infect Immun 76: 2678–2684.

136. WrightAK, BangertM, GritzfeldJF, FerreiraDM, JamboKC, et al. (2013) Experimental human pneumococcal carriage augments IL-17A-dependent T-cell defence of the lung. PLoS Pathog 9: e1003274.

137. Van MaeleL, CarnoyC, CayetD, IvanovS, PorteR, et al. (2014) Activation of Type 3 Innate Lymphoid Cells and Interleukin 22 Secretion in the Lungs During Streptococcus pneumoniae Infection. J Infect Dis 210: 493–503.

138. SpitsH, ArtisD, ColonnaM, DiefenbachA, Di SantoJP, et al. (2013) Innate lymphoid cells–a proposal for uniform nomenclature. Nat Rev Immunol 13: 145–149.

139. TettelinH, NelsonKE, PaulsenIT, EisenJA, ReadTD, et al. (2001) Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science 293: 498–506.

140. LanieJA, NgWL, KazmierczakKM, AndrzejewskiTM, DavidsenTM, et al. (2007) Genome sequence of Avery's virulent serotype 2 strain D39 of Streptococcus pneumoniae and comparison with that of unencapsulated laboratory strain R6. J Bacteriol 189: 38–51.

141. FerrettiJJ, McShanWM, AjdicD, SavicDJ, SavicG, et al. (2001) Complete genome sequence of an M1 strain of Streptococcus pyogenes. Proc Natl Acad Sci U S A 98: 4658–4663.

142. BeresSB, SylvaGL, BarbianKD, LeiB, HoffJS, et al. (2002) Genome sequence of a serotype M3 strain of group A Streptococcus: phage-encoded toxins, the high-virulence phenotype, and clone emergence. Proc Natl Acad Sci U S A 99: 10078–10083.

143. SerriariNE, EocheM, LamotteL, LionJ, FumeryM, et al. (2014) Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases. Clin Exp Immunol 176: 266–274.

144. NakasoneC, YamamotoN, NakamatsuM, KinjoT, MiyagiK, et al. (2007) Accumulation of gamma/delta T cells in the lungs and their roles in neutrophil-mediated host defense against pneumococcal infection. Microbes Infect 9: 251–258.

145. KirbyAC, NewtonDJ, CardingSR, KayePM (2007) Evidence for the involvement of lung-specific gammadelta T cell subsets in local responses to Streptococcus pneumoniae infection. Eur J Immunol 37: 3404–3413.

146. KirbyAC, NewtonDJ, CardingSR, KayePM (2007) Pulmonary dendritic cells and alveolar macrophages are regulated by gammadelta T cells during the resolution of S. pneumoniae-induced inflammation. J Pathol 212: 29–37.

147. SnelgroveRJ, GodleeA, HussellT (2011) Airway immune homeostasis and implications for influenza-induced inflammation. Trends Immunol 32: 328–334.

148. MetzgerDW, SunK (2013) Immune dysfunction and bacterial coinfections following influenza. J Immunol 191: 2047–2052.

149. KawakamiK, YamamotoN, KinjoY, MiyagiK, NakasoneC, et al. (2003) Critical role of Valpha14+ natural killer T cells in the innate phase of host protection against Streptococcus pneumoniae infection. Eur J Immunol 33: 3322–3330.

150. KingIL, AmielE, TigheM, MohrsK, VeerapenN, et al. (2013) The mechanism of splenic invariant NKT cell activation dictates localization in vivo. J Immunol 191: 572–582.

151. IvanovS, FontaineJ, PagetC, Macho FernandezE, Van MaeleL, et al. (2012) Key role for respiratory CD103(+) dendritic cells, IFN-gamma, and IL-17 in protection against Streptococcus pneumoniae infection in response to alpha-galactosylceramide. J Infect Dis 206: 723–734.

152. GalliG, NutiS, TavariniS, Galli-StampinoL, De LallaC, et al. (2003) CD1d-restricted help to B cells by human invariant natural killer T lymphocytes. J Exp Med 197: 1051–1057.

153. GalliG, PittoniP, TontiE, MalzoneC, UematsuY, et al. (2007) Invariant NKT cells sustain specific B cell responses and memory. Proc Natl Acad Sci U S A 104: 3984–3989.

154. LeadbetterEA, BriglM, IllarionovP, CohenN, LuteranMC, et al. (2008) NK T cells provide lipid antigen-specific cognate help for B cells. Proc Natl Acad Sci U S A 105: 8339–8344.

155. TontiE, FedeliM, NapolitanoA, IannaconeM, von AndrianUH, et al. (2012) Follicular helper NKT cells induce limited B cell responses and germinal center formation in the absence of CD4(+) T cell help. J Immunol 188: 3217–3222.

156. KingIL, FortierA, TigheM, DibbleJ, WattsGF, et al. (2011) Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner. Nat Immunol 13: 44–50.

157. ChangPP, BarralP, FitchJ, PratamaA, MaCS, et al. (2011) Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses. Nat Immunol 13: 35–43.

158. KobrynskiLJ, SousaAO, NahmiasAJ, LeeFK (2005) Cutting edge: antibody production to pneumococcal polysaccharides requires CD1 molecules and CD8+ T cells. J Immunol 174: 1787–1790.

159. MiyasakaT, AkahoriY, ToyamaM, MiyamuraN, IshiiK, et al. (2013) Dectin-2-dependent NKT cell activation and serotype-specific antibody production in mice immunized with pneumococcal polysaccharide vaccine. PLoS ONE 8: e78611.

160. MiyasakaT, AoyagiT, UchiyamaB, OishiK, NakayamaT, et al. (2012) A possible relationship of natural killer T cells with humoral immune response to 23-valent pneumococcal polysaccharide vaccine in clinical settings. Vaccine 30: 3304–3310.

161. BaiL, DengS, RebouletR, MathewR, TeytonL, et al. (2013) Natural killer T (NKT)-B-cell interactions promote prolonged antibody responses and long-term memory to pneumococcal capsular polysaccharides. Proc Natl Acad Sci U S A 110: 16097–16102.

162. DengS, BaiL, RebouletR, MatthewR, EnglerDA, et al. (2014) A peptide-free, liposome-based oligosaccharide vaccine, adjuvanted with a natural killer T cell antigen, generates robust antibody responses. Chem Sci 5: 1437–1441.

Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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PLOS Pathogens

2014 Číslo 10
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